The present invention relates to new N-benzylpiperazine compounds and pharmaceutical compositions containing them.
The prior art is illustrated, for example, by:
French Patent Specifications 1 302 958 and 805 M which relate, respectively, to the preparation of N-trialkoxybenzylpiperazines and to the use of 2,3,4-trimethoxybenzylpiperazine as a medicament having vasodilatory activity,
articles by Hiroshi Ohtaka et al., Chem. Pharm. Bull., 35, 2774-3275 (1987) and Chem. Pharm. Bull., 37, 11, 2124-3122 (1989) which mention trimetazidine compounds having a vasodilatory activity, and the synthesis of 1-[bis(4-fluorophenyl)methyl]-4-(2-hydroxy 3,4-dimethoxybenzyl)piperazine,
an article by Tsuneo Kawashima et al., J. Pharmacobio-Dyn, 14, 449-459 (1991) relating to the isolation and identification of new metabolites of KB-2796, including 1-[bis(4-fluorophenyl)methyl]-4-(2-hydroxy 3,4-dimethoxybenzyl)piperazine,
European Patent Specification EP 533 579 which describes N-benzylpiperazine compounds having an antihypoxic and antiischaemic activity,
finally, European Patent Specification EP 617 027 which describes N-benzylpiperazine compounds for use in the treatment of neuronal diseases due to dysfunction of oxidative metabolism.
In addition to being new, the compounds of the present invention have especially innovative pharmacological activity and especially innovative therapeutic properties.
They enable, inter alia, the protection of mitochondria undergoing hypoxic stress, maintenance of the synthesis of ATP in organs starved of oxygen, such as protection of an isolated heart placed in an ischaemic situation. Finally, some are capable of crossing the blood-brain barrier. Those properties therefore make them useful in the prevention or treatment of acute and chronic cellular ischaemia, acute or chronic cerebral, cardiac or peripheral ischaemic accidents, whether followed by reperfusion or not, before any surgical intervention requiring a temporary interruption of blood circulation, locally or generally (tourniquet, clamp), in the treatment of chronic neurodegenerative diseases (such as senile dementia, latent or established Alzheimer""s disease, cerebral ageing, amyotrophic lateral sclerosis, multiple sclerosis or Parkinson""s disease) and in improving the storage of organs intended for transplantation and the resumption of functioning of transplants after reperfusion.
The compounds of the invention also have markedly greater metabolic stability compared with all the compounds of similar structure already described, and thus provide better bioavailability.
More especially, the present invention relates to compounds of formula (I): 
wherein:
R1 represents a linear or branched (C1-C6)alkyl group,
R2 represents a hydroxy group, a linear or branched (C1-C6)alkoxy group, or an amino group (optionally substituted by one or two linear or branched (C1-C6)alkyl groups),
n represents an integer from 1 to 12 inclusive.
R3 represents:
a hydrogen atom,
a linear or branched (C1-C12)alkyl group optionally substituted by a phenyl group (itself optionally substituted by one or more identical or different substituents selected from halogen atoms and linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy and trihalomethyl groups), a (C3-C7)cycloalkyl group, a carboxy group or a (C1-C6)alkoxy-carbonyl group,
a (C3-C7)cycloalkyl group,
a pyrimidinyl group optionally substituted by one or two pyrrolidinyl groups, or
a phenyl group optionally substituted by one or more identical or different substituents selected from halogen atoms and linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy and trihalomethyl groups,
their optical isomers and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein R1 is as defined for formula (I), which is reacted, in the presence of formaldehyde, with a substituted piperazine of formula (III): 
wherein Rxe2x80x23 is as defined for R3 with the exception of an alkyl group substituted by a carboxy group,
to yield a compound of formula (IV): 
wherein R1 and Rxe2x80x23 are as defined hereinbefore,
which is reacted with a compound of formula (V):
Xxe2x80x94(CH2)nxe2x80x94CORxe2x80x22xe2x80x83xe2x80x83(V)
wherein X represents a halogen atom and Rxe2x80x22 represents a linear or branched (C1-C6)alkoxy group, to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1, Rxe2x80x22, Rxe2x80x23 and n are as defined hereinbefore,
which compound of formula (I/a) is converted, if desired,
to the corresponding mono- or di-acid of formula (I/b), a particular case of the compounds of formula (I): 
or to the corresponding amide of formula (I/c): 
wherein R1, R3 and n are as defined for formula (I) and Rxe2x80x32 represents an amino group optionally substituted by one or two linear or branched (C1-C6)alkyl groups,
which compounds of formulae (I/a), (I/b) and (I/c) are purified, if necessary, in accordance with a conventional purification technique, are separated, where appropriate, into their isomers, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base.
The preferred compounds of the invention are those wherein R1 represents a methyl group, R2 represents a hydroxy group and R3 represents a benzyl group, a pyrimidinyl group, a phenyl group preferably substituted by a methoxy group or a hydrogen atom.
The value n is preferably from 1 to 7. More especially, n is 6.
The preferred compounds of the invention are:
7-{6-[(4-benzyl-1-piperazinyl)methyl]-2,3-dimethoxyphenoxy}heptanoic acid and addition salts thereof,
7-{6-{[4-(pyrimidin-2-yl)-1-piperaziny])methyl}-2,3-dimethoxyphenoxy}heptanoic acid and addition salts thereof,
4-{6-[(piperazin-1-yl)methyl]-2,3-dimethoxyphenoxy}butyric acid and addition salts thereof,
7-{6-[(4-(2-methoxyphenyl)-1-piperazinyl)methyl]-2,3-dimethoxyphenoxy}heptanoic acid and addition salts thereof,
4-{6-[(4-(2-methoxyphenyl)-1-piperazinyl)methyl]-2,3-dimethoxyphenoxy}butyric acid and addition salts thereof.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) alone or in combination with one or more inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, cutaneous administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, and may be oral, nasal, rectal or parenteral. Generally, the unit dose ranges from 0.1 to 500 mg per 24 hours for treatment in from 1 to 3 administrations.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials used are known products or are prepared according to known procedures.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).